Kallikreins belong to a family of serine proteases capable of cleaving various substrates and generating biologically active peptides. In spite of the names, tissue or glandular kallikreins should be distinguished from plasma kallikrein. They differ from plasma kallikrein in their genes of origin, molecular weight, amino acid sequences, substrates, peptide products and most probably physiological functions. There are at least 20 genes for tissue kallikrein in rodents (98), while in humans 15 genes have been so far described (Yousef, G. M., Scorilas, A., Jung, K., Ashworth, L. K., Diamondis, E. P. J. Biol. Chem. 2001, 276:53–61; Clements, J., Hooper, J., Dong, Y., Harvey, T. Biol. Chem. 2001, 382:5–14). Of these, only one gene in each species codes for true glandular kallikrein. Of the rat genes at least 6–7 appear to be expressed in the submandibular (SM) gland (99). These include true glandular kallikrein, tonin, α and γ nerve growth factor (NGF), and the epidermal growth factor (EGF)-binding protein (EGF-BP), type A, B, and C. As used herein, the term “glandular kallikrein (GK)” refers to true GK, while the general term “kallikrein(s)” (K), will be used for any unspecified members of the tissue kallikrein family. True GK has been designated in various species as kallikrein −1 (K1) (100).
The best known substrates for GK-action are hepatic-derived kininogens (100) which occur in two forms: low molecular weight kininogen (50 kDa) and high molecular weight kininogen (120 kDa). From the action of plasma kallikrein on high molecular weight kininogen a nonapeptide, bradikinin, is generated, while in most species GK gives rise to a decapeptide, kallidin (lys-bradikinin) from either low or high molecular weight kininogen. Kallidin is biologically active in itself but may also be further processed into bradikinin. An exception may be the GK of the rat SMG which was reported to produce bradikinin (101).
While the action of GK on kininogen is particularly well studied, the full range of GK substrates has not yet been investigated. Since GK is, and most of the times remains, localized in certain tissues, physiological substrates are likely to vary from tissue to tissue. Of particular interest here is the possibility that GK may activate or in any way regulate some other immunologically active factors of the SM gland, including NGF, EGF/transforming growth factor (TGF)-α and TGFβ. Thus, salivary gland GK may exert its immunological effects either via the production of classical kinins; or via other immunologically active factors. Moreover, salivary GK is actively secreted in saliva (102) and would be expected to reach various points in the gastrointestinal tract and act on various substrates there.